Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/21—Interferons [IFN]
  • A61K38/212—IFN-alpha
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system

Definitions

• the present invention relates to a medicament for animals directed to cats, more particularly to a therapeutic agent for cat respiratory diseases which contains a human interferon(s) (sometimes abbreviated as "HuIFN(s)” hereinafter) as an effective ingredient.
• a human interferon(s) sometimes abbreviated as "HuIFN(s)” hereinafter
• feline cold Excluding cats with traumas and fractures requiring surgery, the number of other cats suffering from infectious diseases, especially respiratory diseases, i.e. "feline cold", and being brought to veterinary hospitals, is increasing.
• the main inducer of feline cold has been deemed to be viruses which infect feline airways, and felines infected with viruses mostly show common cold-like symptoms such as cough, rhinorrhea, drooling, fever, inflammation of superior airway, pneumonia, stomatitis, glossitis, conjunctivitis, granular adenitis, lingual ulcer, ulcer of nasal end, systematic skin ulcer, turbinal ulcer, scours, vomiting, anorexia and reduction of vitality.
• felines when felines are infected with feline immunodeficiency virus (sometimes abbreviated as "FIV” hereinafter), they become more likely to show the above-mentioned symptoms and rapidly weaken.
• feline virus diseases as well as feline respiratory diseases, and actually these diseases are only treated with symptomatic treatments such as trophotherapy by administering to felines to be treated nutrient feeds in order to relieve their dehydration symptoms and to recover their physical vitality, as well as administering antibiotics to them to prevent multiple or secondary infections, and physically removing viscous secreta.
• the object of the present invention is to provide a therapeutic agent for cat respiratory diseases which exerts a satisfactorily-high efficacy even when administered to cats via administrations excluding intravenous administration, and to reduce the burdens and labor to veterinaries who treat cats, as well as reduce the cost of treatment to the owners.
• HuIFNs exert a strong efficacy on the improvement of cats with clinical symptoms in general such as cough, rhinorrhea, drooling, fever, inflammation of superior airway, pneumonia, stomatitis, glossitis, conjunctivitis, granular adenitis, lingual ulcer, ulcer of nasal end, systematic skin ulcer, turbinal ulcer, scours, vomiting, anorexia and reduction of vitality.
• the administrations of HuIFNs are not restricted to intravenous administration, and can be arbitrarily administered to cats by other administrations such as oral- and parenteral-administrations.
• the present inventors accomplished a therapeutic agent for cat respiratory diseases which contains an HuIFN as an effective ingredient.
• interferons IFNs
• IFNs interferons
• the HuIFNs used as an effective ingredient in the present therapeutic agent effectively act on cats suffering from respiratory diseases and improve their clinical symptoms in general which were accompanied by the diseases, for example, cough, rhinorrhea, drooling, fever, inflammation of superior airway, pneumonia, stomatitis, glossitis, conjunctivitis, granular adenitis, lingual ulcer, ulcer of nasal end, systematic skin ulcer, turbinal ulcer, scours, vomiting, anorexia and reduction of vitality.
• diseases for example, cough, rhinorrhea, drooling, fever, inflammation of superior airway, pneumonia, stomatitis, glossitis, conjunctivitis, granular adenitis, lingual ulcer, ulcer of nasal end, systematic skin ulcer, turbinal ulcer, scours, vomiting, anorexia and reduction of vitality.
• the HuIFNs used in the invention exert a relatively-high efficacy on cat respiratory diseases, and, usually the desired efficacy is attained with only a small dose of about 0.005-5,000 international units of the HuIFNs per kg of cat.
• the HuIFNs exert a strong therapeutic efficacy on cat respiratory diseases even when administered to them orally and parenterally, as well as intravenously.
• cat(s) as referred to in the invention means felid(s) or feline(s) of the genus Felis in general who is susceptible to airway-infectious viruses such as feline herpes virus and calicivirus, and shows one or more clinical symptoms in general selected from cough, rhinorrhea, drooling, fever, inflammation of superior airway, pneumonia, stomatitis, glossitis, conjunctivitis, granular adenitis, lingual ulcer, ulcer of nasal end, systematic skin ulcer, turbinal ulcer, scours, vomiting, anorexia and reduction of vitality when it is infected with the above-mentioned viruses or further infected multiply or successively with FIV, mycoplasma, bacteria or parasites.
• the therapeutic agent according to the present invention is usually directed to tame cats in general.
• the present therapeutic agent according to the present invention contains as an effective ingredient an interferon derived from human cells or recombinant microorganisms and animal cells into which an HuIFN related gene, prepared from human cells, has been introduced.
• HuIFNs are mainly classified into 3 types, namely HuIFN- ⁇ , HuIFN- ⁇ and HuIFN- ⁇ based on their antigenicity. These HuIFNs can be used in the present invention, though they show a slight difference in their therapeutic efficacy on cat respiratory diseases.
• the HuIFNs can be used alone or in combination with two or more different types of interferons.
• HuIFNs with the highest possible specific activity it is preferable to use the HuIFNs with the highest possible specific activity, and partially or completely purified specimens with a specific activity of about 10 5 international units/mg protein or higher can be favorably used for oral use, while purified HuIFN specimens with a specific activity of about 10 7 international units/mg protein or higher can be favorably used for parenteral use.
• HuIFN- ⁇ particularly, "a natural HuIFN- ⁇ ", produced by leukocytes isolated from human blood or by human lymphoblastoid cell lines such as BALL-1 cells and Namalwa cells, is characteristic in that it exerts a relatively-high therapeutic efficacy on cat respiratory diseases with only a relatively-low level of side effects.
• the HuIFN- ⁇ derived from BALL-1 cells, containing interferon subtypes ⁇ 2 and ⁇ 8 in a satisfactorily balanced ratio exerted the maximum therapeutic efficacy when used in the present invention.
• recombinant HuIFNs seemed to be inferior to natural HuIFNs in the therapeutic efficacy, and showed a tendency to cause a slightly-higher level of side effects.
• the present therapeutic agent for cat respiratory diseases includes those consisting of HuIFNs alone or in combination with other physiologically acceptable substances such as a carrier, excipient, diluent, adjuvant and stabilizer, and, if necessary antipyretic, anti-inflammatory agent, antibacterial agent, digestion accelerating agent, nutrient agent and feed.
• the present therapeutic agent includes those in the form of a unit dose which contain an HuIFN in an amount requisite for one day dose or in an amount of 1/40 to 4 times of the daily dose.
• the therapeutic agents in the form of a unit dose mean those in the form of a physically separated agent, for example, those in the form of an injection, liquid, orally administrable gel agent, powder, granular, tablet, capsule and sublingual.
• the present therapeutic agent exerts the desired therapeutic efficacy whenever administered to cats orally and parenterally.
• the dose varies dependently on the species of cats, the variety of causative virus, symptoms of cats, amounts of the HuIFNs used in the invention, administration routes, and interferon types to be used, the HuIFNs are usually administered to cats 1-3 times a day or 1-5 times a week at a dose of about 0.005-5,000 international units, preferably about 0.5-50 international units, more preferably about 1-20 international units per shot over a period of about one day to one month.
• the present therapeutic agent When the present therapeutic agent is administered to cats orally, it is first prepared into an orally administrable form such as a liquid, troche, powder, granule, tablet, sublingual and feed, then administered to the cats in usual manner into their oral-, nasal-, esophagus- and gastric-cavities by using adequate supplementary administration aids such as a sound and instrument for oral administration.
• an orally administrable form such as a liquid, troche, powder, granule, tablet, sublingual and feed
• supplementary administration aids such as a sound and instrument for oral administration.
• the present therapeutic agent in the form of injection it can be administered to them intracutaneously, subcutaneously, intravenously and intraperitonealy.
• oral administration When compared the administration routes in terms of their therapeutic efficacy and readiness of administrations, oral administration has an advantage of being readily conducted at each owner's home in general, but has the disadvantage of being not readily conducted to administer a prescribed amount of HuIFN to cats. This may result in an excessive amount of an HuIFN administration as compared with the desired doses, as well as in a relatively-long period of time for therapy and a heavy economical burden to cat owners.
• parenteral administration has the disadvantage of being not readily conducted at each owner's home in general, but has an advantage of being conducted to administer an accurate amount of HuIFN to the cats, and being attainable of the desired therapeutic efficacy with only the minimum dose of HuIFN.
• the parenteral administration attains the complete treatment of cats within the shortest possible period of time, and lowers the owners's economical burden. More particularly, the intracutaneous-, subcutaneous- and intramuscular-administrations of the present therapeutic agent are readily conducted and attain the desired therapeutic efficacy with only a small amount of HuIFN than in the case of the oral administration and other administrations excluding the aforesaid administrations, as well as satisfactorily reducing the owners's economical burden.
• These advantageous features were more distinct in the case of natural HuIFNs, more particularly HuIFN- ⁇ derived from BALL-1 cells.
• the HuIFN activity is expressed with "international interferon units": Assaying an HuIFN specimen on the microtiter technique for determining the degree of the cytopathic-inhibitory activity of Sindbis virus on FL cells, and calculating the activity based on an activity obtained with "Ga23-901-532", an international HuIFN standard of National Institutes of Health, U.S.A.
• BALL-1 cells proliferated in hamsters were subjected to the action of sendai virus (HVJ) in a nutrient culture medium to induce an interferon.
• HVJ sendai virus
• the resultant culture was centrifuged to obtain a supernatant which was then concentrated and partially purified on affinity chromatography using phenyl sepharose to obtain a partially purified HuIFN with a specific activity of about 10 6 international units/mg protein.
• the partially purified HuIFN was in usual manner further purified on affinity chromatography using "NK-2 SEPHAROSE", a product of Celltech Ltd., Berks, England, wherein an anti-HuIFN- ⁇ monoclonal antibody was immobilized on water-insoluble carriers, and subjected to gel filtration chromatography using a gel column equilibrated with phosphate buffer (pH 7.0) containing about 0.1 mg/ml of cat serum albumin.
• phosphate buffer pH 7.0
• the solution thus obtained was concentrated with a membrane filter into a solution containing about 5 mg protein/ml HuIFN- ⁇ which was then diluted with a physiological saline containing one w/v % cat serum albumin and 0.01 M phosphate buffer (pH 7.0) to obtain a solution with a concentration of 15 international units/ml of the HuIFN- ⁇ , followed by membrane filtration and sterilization thereof.
• a physiological saline containing one w/v % cat serum albumin and 0.01 M phosphate buffer (pH 7.0) to obtain a solution with a concentration of 15 international units/ml of the HuIFN- ⁇ , followed by membrane filtration and sterilization thereof.
• One ml aliquots of the resultant solution were aseptically injected into vials and lyophilized.
• the product contains an HuIFN- ⁇ derived from BALL-1 cells as an effective ingredient and a serum albumin from cat as an excipient, it can be favorably used as a therapeutic agent for cat respiratory diseases.
• HVJ sendai virus
• the partially purified HuIFN was successively purified on affinity chromatography using an anti-HuIFN- ⁇ monoclonal antibody, and gel filtration chromatography using a gel column equilibrated with a phosphate buffer (pH 7.0) containing about 0.1 mg/ml of a purified gelatin as listed in the Pharmacopoeia of Japan to obtain an HuIFN- ⁇ solution containing a purified HuIFN- ⁇ with a specific activity of about 2 ⁇ 10 8 international units/mg protein.
• a phosphate buffer pH 7.0
• the solution thus obtained was concentrated with a membrane filter into a solution containing about 5 mg protein/ml of the HuIFN- ⁇ , which was then diluted with a physiological saline containing 0.01 M phosphate buffer (pH 7.0) and 1 w/v % purified gelatin as listed in Pharmacopoeia of Japan into a solution with a concentration of 20 international units/ml of the HuIFN- ⁇ , followed by membrane filtration and sterilization thereof.
• One ml aliquots of the resultant solution were aseptically injected into vials and lyophilized.
• the product containing the HuIFN- ⁇ derived from human leukocytes as an effective ingredient, is slightly inferior to the product in Example 1 in terms of therapeutic effect and side effects, it can be favorably used as a therapeutic agent for cat respiratory diseases.
• Example 2 a purified HuIFN- ⁇ specimen, prepared by allowing sendai virus (HVJ) to act on BALL-1 cells, was diluted in physiological saline containing 3 w/v % cat serum albumin and 0.1 M phosphate buffer (pH 7.0) to give a concentration of 20,000 international units of the HuIFN- ⁇ .
• the resultant solution was membrane filtered, sterilized and injected into vials by one ml.
• the product in Example 1 containing a purified HuIFN- ⁇ derived from BALL-1 cells as an effective ingredient and a serum albumin derived from cat as an excipient, can be suitably used as a therapeutic agent for cat respiratory diseases.
• One w/v % calf serum albumin was dissolved in distilled water, and the resultant solution was mixed with a solution containing a partially purified HuIFN derived from BALL-1 cells prepared by the method in Example 1 into an HuIFN solution containing 300 international units of the HuIFN per g.
• Thirty-three parts by weight of the solution was mixed with a solution prepared by dissolving 0.5 parts by weight of "Tween 80", a surfactant, in 15.0 parts by weight of ethanol, and the resultant mixture was mixed with a solution prepared by dissolving 0.5 parts by weight of triethanolamine in 15.0 parts by weight of glycerine.
• To the resultant mixture was added a small amount of triethanolamine to obtain a roughly neutral gel preparation containing about 100 international units of the HuIFN per ml.
• the product which contains an HuIFN derived from BALL-1 cells as an effective ingredient and has an appropriate residence time in cat mouths, is a readily-swallowable oral gel agent for cat respiratory diseases.
• FINETOSE® a high-purity anhydrous crystalline maltose commercialized by Hayashibara Co., Ltd., Okayama, Japan
• FINETOSE® a high-purity anhydrous crystalline maltose commercialized by Hayashibara Co., Ltd., Okayama, Japan
• a solution containing about 10 6 international units/ml of a partially purified HuIFN derived from human leukocytes prepared by the method in Example 2 was dried in vacuo, pulverized and sieved to obtain granules having a grain size of 100-500 ⁇ m.
• the granules were mixed to homogeneity with an adequate amount of "FINETOSE®” to obtain a powdered agent containing about 100 international units of the HuIFN per g, d.s.b.
• the product which has a satisfactory storage stability and an appropriate residence time in cat mouths, is suitably used as a therapeutic agent for cat respiratory diseases.
• the product is a readily-swallowable powdered agent which has a moderate sweetness and less stimulates cat mouths when administered to their oral cavities.
• the product is a readily-swallowable granule for cats because it has a moderate sweetness and less stimulates the oral cavities when orally administered.
• Fifty-two tame cats were actually administered with the present therapeutic agent and observed their symptoms, and the therapeutic efficacy and side effects were evaluated, wherein said cats, which had been mainly suffering from cough, rhinorrhea, drooling, fever, inflammation of superior airway, pneumonia, stomatitis, glossitis, conjunctivitis, granular adenitis, lingual ulcer, ulcer of nasal end, systematic skin ulcer, turbinal ulcer, scours, vomiting, anorexia and reduction of vitality, were brought to a veterinary hospital and diagnosed as cat respiratory diseases.
• the cats were carefully observed, and the administration doses and the following 14 clinical symptoms in general such as systematic conditions, dehydrating conditions, appetites, requiring for water, activities, rhinorrhea, cough, scours, drooling, conjunctivitis, stomatitis, ulcer of nasal end, respirating conditions, and vomiting were recorded.
• the virus diagnosis of the cats revealed that most of the cats were suspicious of a multiple infection of FIV and cat herpes virus and/or cat calicivirus.
• the veterinarians mainly conducted the clinical test and controlled the dose and administration frequency of interferon while observing the conditions and symptoms of cats as well as side effects. After completion of the administrations, the results were put together and the therapeutic efficacy of the dehydrated injection was evaluated based on the following criteria: Cats who recovered their health within 5 days were evaluated as "Superior”; those, wherein the symptoms of stomatitis were improved as compared with those in their first medical examinations, and 3 or more other symptoms were improved or 5 of the other symptoms were improved without causing stomatitis, were evaluated as "Effective”; those, wherein the symptoms of stomatitis were not improved but 4 or more other symptoms were improved, were evaluated as "Slightly effective”; those, who showed no improvement in their symptoms, were evaluated as "Non effective”; and those, wherein the symptoms were worsened, were evaluated as "Inferior".
• the therapeutic agents in Examples 2, 4 and 5 were similarly subjected to their clinical tests which resulted in an exertion of a relatively-high therapeutic efficacy, i.e. their therapeutic efficacy were about 70% or higher when parenterally administered and about 60% or higher when orally administered.
• the efficacy of the oral administrations was slightly lower than that of the parenteral administrations but it was far higher than those of medicaments in general. Since the parenteral administrations were conducted by intradermal-, intraperitoneal-, intramuscular-, intravenous- and intraperitoneal-injection with only a small amount of dose, the time required for such an injection was relatively short, and almost every injection completed with only one shot without letting nearly all the cats go wild.
• the veterinarians mainly conducted the clinical test and controlled the dose and the administration frequency of interferon while observing side effects as well as conditions and symptoms of the cats. After completion of the administrations, the results were put together and the therapeutic efficacy of the dehydrated injection was evaluated based on the same criteria as indicated in Experiment reference 1.
• results in the clinical test revealed that all the cats were improved their symptoms immediately after the initiation of administration, and they recovered from cough, rhinorrhea, drooling and scours within 3 days, and recovered their normal temperatures in the level of 37° C. They were also remarkably improved their health or even cured from inflammation of superior airway, stomatitis, conjunctivitis, and ulcer of nasal end within a week after the initiation of administration, as well as being improved their appetite and activity.
• Example 6 Based on the above findings, the therapeutic agent in Example 6 was similarly subjected to its clinical test, and this resulted in a relatively-high therapeutic efficacy, i.e. the therapeutic efficacy was about 75% or higher even when administered orally.
• the efficacy attained by the oral administration was slightly lower than that attained by the parenteral administrations but the efficacy was far higher than that attained by conventional medicaments.
• the present therapeutic agent for cat respiratory diseases which contains an HuIFN as an effective ingredient satisfactorily improves the cat clinical symptoms in general such as cough, rhinorrhea, drooling, fever, inflammation of superior airway, pneumonia, stomatitis, glossitis, conjunctivitis, granular adenitis, lingual ulcer, ulcer of nasal end, systematic skin ulcer, turbinal ulcer, scours, vomiting, anorexia and reduction of vitality.
• the present therapeutic agent reduces the owners's economical burden by a large margin because it contains as an effective ingredient HuIFNs which can be administered to cats without a fear of causing side effects even if administered to them with a relatively-large amount, and exert a strong efficacy on the aforementioned clinical symptoms with only a small amount.
• the present therapeutic agent renders the intravenous administration of human interferons unnecessary, and attains the desired efficacy even when administered to cats via the oral and parenteral routes such as intradermal-, subcutaneous- and intramuscular-administrations.
• the present therapeutic agent does facilitate the administration of a prescribed amount of HuIFNs to nervous and careful cats without fail, and reduces the labor and burden of veterinaries as well as their assistants by a large margin.

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Citations (7)

• 1994
  • 1994-04-08 EP EP94302484A patent/EP0619120B1/de not_active Expired - Lifetime
  • 1994-04-08 DE DE69431320T patent/DE69431320T2/de not_active Expired - Fee Related
• 1995
  • 1995-12-22 US US08/578,060 patent/US5942224A/en not_active Expired - Fee Related

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